The formation, survival, and growth of the primordial follicle pool in the mammalian ovary are dynamic processes regulated by a variety of autocrine, paracrine, and endocrine signals. Although often considered to be a relatively quiescent and resting population, primordial follicles are nevertheless unusually susceptible to destruction and damage by environmental and chemical agents. It is also a difficult population to study given the marked variability that exists in primordial follicle endowment between individuals, even within a given species. Among the many autocrine/paracrine regulators of ovarian function that have been identified, the role of the GnRH/GnRH receptor system in the ovary has received renewed interest. It is now evident that 2 forms of GnRH and their cognate receptors are present in the ovaries of many mammals including primates. Direct effects of GnRH agonists on the ovary are well established, and although newer, GnRH antagonists have also been demonstrated to directly modulate ovarian function. We have recently demonstrated a rapid and pronounced destruction of primordial follicles in the mouse ovary by short-term treatment with GnRH antagonists. We hypothesize that new, highly potent GnRH antagonists currently in clinical use may have similar adverse effects on the primordial follicle reserve in the primate ovary. As such, the primary goal of the present proposal is to determine whether GnRH antagonists destroy primordial follicles in a primate model of human reproduction. To test this hypothesis, we propose to determine the effects of GnRH antagonist treatment on the number of primordial follicles in the cynomolgus monkey. In addition, to identify the potential cellular targets (and sources) of GnRH in the primate ovary, we will measure the expression of the GnRH/GnRH receptor system using laser capture micro-dissection and real-time PCR. These experiments will provide the first detailed information on the effects of GnRH antagonists on primordial follicle survival in the primate ovary. In addition, cellular localization of the GnRH/GnRH receptor system in the primate ovary will provide important insight into the potential ovarian mechanisms of action of GnRH and its analogs. As newer and more potent GnRH antagonists enter clinical use, especially for the treatment of otherwise healthy fertile women, their potential effects on primordial follicle survival and ovarian senescence must be identified. [unreadable] [unreadable] [unreadable]